Investigation on the sucrose binding pocket of HIV-1 Integrase by molecular dynamics and synergy experiments

Cristina Tintori; Francesca Esposito; Francesca Morreale; Riccardo Martini; Enzo Tramontano; Maurizio Botta

doi:10.1016/j.bmcl.2015.05.011

Investigation on the sucrose binding pocket of HIV-1 Integrase by molecular dynamics and synergy experiments

Bioorg Med Chem Lett. 2015 Aug 1;25(15):3013-6. doi: 10.1016/j.bmcl.2015.05.011. Epub 2015 May 15.

Authors

Cristina Tintori¹, Francesca Esposito², Francesca Morreale³, Riccardo Martini¹, Enzo Tramontano², Maurizio Botta⁴

Affiliations

¹ Dipartimento Biotecnologie, Chimica e Farmacia, Università degli Studi di Siena, via A. Moro, 53100 Siena, Italy.
² Department of Life and Environmental Sciences, University of Cagliari, Cittadella Universitaria di Monserrato, Monserrato, Italy.
³ Dipartimento di Scienze del Farmaco e dei Prodotti per la Salute, Università di Messina, Viale Annunziata, I-98168 Messina, Italy.
⁴ Dipartimento Biotecnologie, Chimica e Farmacia, Università degli Studi di Siena, via A. Moro, 53100 Siena, Italy; Sbarro Institute for Cancer Research and Molecular Medicine, Center for Biotechnology, College of Science and Technology, Temple University, BioLife Science Bldg., Suite 333, 1900 N 12th Street, Philadelphia, PA 19122, USA. Electronic address: botta.maurizio@gmail.com.

PMID: 26048795
DOI: 10.1016/j.bmcl.2015.05.011

Abstract

Enzymes whose catalytic activity depends on multimeric assembly are targets for inhibitors that perturb the interactions between the protein subunits such as the HIV-1 Integrase (IN). Sucrose has been recently crystallized in complex with IN revealing an allosteric binding pocket at the monomer-monomer interface. Herein, molecular dynamics were applied to theoretically test the effect of this small ligand on IN. As a result, such a compound increases the mutual free energy of binding between the two interacting monomers. Biological experiments confirmed the computational forecast.

Keywords: HIV-1 Integrase; Molecular dynamics; Protein–protein interaction; Sucrose.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Binding Sites
Drug Synergism
HIV Infections / drug therapy
HIV Infections / virology
HIV Integrase / chemistry
HIV Integrase / metabolism*
HIV Integrase Inhibitors / pharmacology*
HIV-1 / drug effects
HIV-1 / enzymology*
Humans
Molecular Docking Simulation
Molecular Dynamics Simulation
Protein Binding
Protein Multimerization / drug effects
Raltegravir Potassium / pharmacology
Sucrose / pharmacology*
Thermodynamics

Substances

HIV Integrase Inhibitors
Raltegravir Potassium
Sucrose
HIV Integrase
p31 integrase protein, Human immunodeficiency virus 1